Intravascular ultrasound (IVUS) is an established tool for obtaining ultrasound images within the vascular system. IVUS is a method by which a catheter-based high frequency (e.g., 20 to 50 MHz) transducer is used to create high resolution images of the lumen and vascular wall of larger vessels. It is an established interventional cardiology tool for gaining insight into the size, structure, and composition of atherosclerotic plaque located within coronary arteries.
FIG. 1 shows an exemplary IVUS catheter within a body lumen. The IVUS catheter comprises a transducer at its distal end for obtaining ultrasound images from within the body lumen. The transducer may be comprised of a single element transducer that mechanically scans to create a cross-sectional image, e.g., by rotating the transducer with a drive shaft and having the transducer transmit pulses as it rotates. Current high frequency imaging systems employ a mechanically scanned single element transducer and single pulse per line image formation
Ultrasound images may also be obtained using an array of transducer elements that electronically scans an image. Three-dimensional (3D) imaging may be performed using a two-dimensional (2D) imaging array by mechanically moving the 2D imaging array to obtain 2D images at different positions and combining the 2D images to form a 3D image. 3D images may also be obtained using a single transducer element. This may be done by rotating the transducer to obtain 2D images, moving the transducer laterally (e.g., pulling back the transducer) to obtain 2D images at different locations, and combining the 2D images to form a 3D image.
Nonlinear tissue imaging techniques have also been developed. In this case, nonlinear propagation of an ultrasound pulse through tissue within the body (increasing with transmit pressure) gives rise to harmonics of the transmit frequency (centered at approximately positive integer multiples of the transmit frequencies). A nonlinear imaging system generates ultrasound images using the nonlinear echoes arising from nonlinear interactions of the transmitted ultrasound pulses with tissue. The nonlinear echoes may be second harmonic (twice the transmit frequency), or combinations of second and higher order harmonics, referred to as superharmonic imaging, as described by Ayache Bouakaz et al., “Native tissue imaging at superharmonic frequencies,” IEEE Trans Ultrason Ferroelec Freq Control, Vol. 50, No. 5, pp. 496-506, 2003, which is incorporated herein by reference. The formation of nonlinear tissue images can result in a reduction of imaging artifacts and thereby improve image quality. Nonlinear imaging requires isolation of the nonlinear echoes by suppressing the fundamental frequency (i.e., transmit frequency). The fundamental frequency may be suppressed using a pulse inversion (PI) technique, bandpass filtering, or a combination of these approaches. The basic PI technique, as described by David H. Hope Simpson et al., “Pulse inversion doppler: A new method for detecting nonlinear echoes from microbubble contrast agents,” IEEE Trans Ultrason Ferroelec Freq Control, Vol. 46, No. 2, pp. 372-382, 1999, which is incorporated herein by reference, involves transmitting a pulse and its inverted counterpart along each scan line to cancel out the fundamental signal. A primary advantage of this approach is that it does not require separate frequency bands for the fundamental and harmonic signals, and thereby permits the use of wider bandwidth transmit signals, which can potentially overlap with the nonlinear signals. Wide bandwidth transmit signals in turn improve the axial resolution of the imaging system.
An application of IVUS tissue harmonic imaging is to improve the image quality of atherosclerotic plaque imaging, which may in turn improve diagnosis, treatment planning and therapeutic monitoring. Image artifacts that may be improved with such an approach are catheter sheath artifacts, stent reverberation artifacts, and the presence of calcification within plaques.
Ultrasound contrast imaging employs a contrast agent to enhance the detection and imaging of blood flow or blood vessels within the body. The contrast agent may be comprised of echogenic microbubbles having ultrasound scattering properties that are distinct from those of tissue, thereby enhancing contrast between sites containing the microbubbles and surrounding tissue. Microbubbles are encapsulated gas bubbles of diameters small enough to pass through the capillary beds (typically <10-12 microns) dispersed in an aqueous medium, and may be injected into the blood stream in order to enhance detection of blood vessels (e.g., microvessels) at the imaging location. Typically contrast agents are designed to contain substantial numbers of bubbles of a size that is resonant, or acoustically active at diagnostic ultrasound frequencies (2-10 microns in diameter). These bubbles may have bubbles below 2 microns present, or below 1 micron present. Bubbles can be made to have most bubbles on the order of 1-2 microns in diameter and below. Microbubbles are encapsulated with either a stiff shell or stabilized with a surfactant shell that is compliant (e.g., lipids, albumin). This shell can affect the mechanical properties of bubbles. Microbubbles may also be employed to target (i.e. attach through interaction between molecules within or attached to the microbubble shell and molecular epitopes of interest expressed by tissue within the body) molecules of interest within the body. This may be achieved by introducing these bubbles into the body and allowing their accumulation at a sight of interest and then imaging them. Microbubbles can be induced to exhibit scattering properties that are different from those of tissue. For example, microbubbles can emit second harmonic signals (at different pressure levels than those required to generate tissue harmonics), superharmonic signals, subharmonic signals (particularly but not exclusively centered near at ½ the transmit frequency), ultraharmonic signals (particularly but not exclusively at 1.5, 2.5, 3.5 etc of the transmit frequency. Microbubbles can be destroyed, thereby enabling the implementation of indicator dilution techniques. During destruction, broadband acoustic emissions can be made, and interpulse decorrelation can occur. Transient bubble behavior, sensitive to pulse frequency shape and phase, can also be stimulated. Microbubbles are more acoustically active in the vicinity of their resonant frequencies, though advantageous emissions can be induced when transmitting below the resonant frequency (e.g., second harmonic or destruction) or above (e.g., subharmonics). Bubble resonant frequencies are higher for smaller bubbles. In IVUS frequency ranges nonlinear activity of bubbles has been detected in bubbles on the order of 2 microns and below.
All of the above behaviors, and others can be used either alone or in combination to improve the detection of microbubbles in the presence of tissue for the purposes of improved blood compartment or molecular detection. Examples of microbubbles are disclosed in WO 2006/015876, WO 97/29783, WO 2004/0069284, U.S. Pat. No. 5,271,928, U.S. Pat. No. 5,445,813, U.S. Pat. No. 5,413,774, U.S. Pat. No. 5,597,549, U.S. Pat. No. 5,827,504, U.S. Pat. No. 5,711,933, and U.S. Pat. No. 6,333,021, all of which are incorporated herein by reference.
One application of IVUS contrast imaging is in the detection, visualization and quantification of vasa vasorum in or surrounding atherosclerotic plaques. This would be done for the purposes of diagnosis, treatment planning and therapeutic monitoring. This would be achieved by applying bubble detection procedures following either the local or systemic injection of untargeted contrast agent. The vasa vasorum are microvessels surrounding and penetrating the walls of larger blood vessels. While their precise role is not entirely understood, evidence is mounting that the growth of neovascular vasa vasorum through the process of angiogenesis is a crucial step in the development of atherosclerotic plaques. This realization has led to an emerging interest in the vasa vasorum as a therapeutic target and a growing demand for vasa vasorum imaging techniques. These techniques could also be used in conjunction with tissue structure information provided by IVUS. For example to determine the location of vascularity relative to plaque structure, potentially useful information. In addition to untargeted agent, targeted contrast agents are also considered for this application. For example, targeting to neovascular endothelial cell markers. Agent could also be targeted to other molecules of interest in atherosclerosis.
Recently, the feasibility of performing both second harmonic and wide bandwidth subharmonic contrast imaging with an IVUS system operating at high frequencies has been demonstrated by David E. Goertz et al., “Nonlinear Intravascular Ultrasound Contrast Imaging,” Ultrasound in Med & Biol., Vol. 32, No. 4, pp. 491-502, 2006, which is incorporated herein by reference. These nonlinear contrast imaging approaches provide a promising means for improving vessel lumen boundary detection and IVUS vasa vasorum imaging.
As discussed above, in nonlinear imaging applications, it is important to achieve effective suppression of the fundamental signal. The basic pulse inversion (PI) technique its widely used for fundamental suppression. However, the effectiveness of the basic PI technique is reduced by transducer motion and the relative motion between the transducer and tissue, which cause the fundamental echoes arising from a transmitted pulse and its inverted counterpart to not cancel out completely. The reduction in the effectiveness of the PI technique was demonstrated for a mechanically rotating transducer of an IVUS catheter by Martin E. Frijlink et al. “A simulation Study on Tissue Harmonic Imaging with a Single-element Intravascular Ultrasound Catheter,” J. Acoust. Soc. Am., Vol. 120, No. 3, September 2006, which is incorporated herein by reference.
Because mechanical scanning requires moving the transducer, nonlinear imaging systems using mechanical scanned transducers suffer greater degradation in fundamental frequency suppression due to motion effects compared with array-based imaging system where the transducers are normally stationary and electrically scanned. 3D imaging using a 2D array-based system also suffers degradation in fundamental frequency suppression due to motion effects because the array has to be mechanically moved to obtain 2D images at different positions to form the 3D image.
Therefore, there is a need to improve fundamental frequency suppression for nonlinear imaging systems using mechanically scanned transducers.
Many nonlinear imaging approaches would benefit from improved fundamental frequency suppression. For example, the nonlinear ultrasound contrast imaging approaches discussed above would benefit from improved fundamental frequency suppression. Examples of other imaging approaches that may benefit from improved fundamental frequency suppression include, but are not limited to:
1. Broadband signals from bubble disruption. Fundamental suppression is key for discriminating broadband contrast signals from tissue signals.
2. ‘Pulse-inversion fundamental’ techniques, which take advantage of energy in the transmit frequency range, which can be present for a number of reasons (e.g., broadening of the fundamental frequency response, asymmetric bubble responses to compressional and rarefactional cycles). A pulse-inversion-based fundamental imaging technique has been described by Che-Chou Shen and Pai-Chi Li, “Pulse-inversion-based fundamental imaging for contrast detection,” IEEE Trans Ultrason Ferroelec Freq Control, Vol. 50, No. 9, pp. 1124-1133, 2003, which is incorporated herein by reference. Transducer motion reduces the ability to use Fundamental frequency energy originating from bubble vibrations or reflections.
3. Dual frequency approaches, whereby a low frequency signal modulates the high frequency scattering response from bubbles, as described in the patents WO 2005/071437A1 and WO 2006/001697A2, which are incorporated herein by reference. In this case bubbles are detected in the high frequency transmit bandwidth, using differences from the bubbles during low frequency compression and rarefaction cycles. A key to the success of this technique is to achieve the effective suppression of the tissue signal at high frequencies, through for example pulse inversion (or subtraction in post-processing) techniques, which can be corrupted by relative tissue and transducer motion.
4. ‘Repetition rate imaging’, where larger bubbles are stimulated to oscillate by sending high frequency ultrasound pulses at a pulse repetition frequency (PRF) at or near the bubble resonant frequencies, as described by Hendrik J. Vos et al., “Repetition rate imaging of bubbles”, abstract of the Eleventh European Symposium on Ultrasound Contrast Imaging, Rotterdam, the Netherlands, Jan. 26-27, 2006, which is incorporated herein by reference. Differences between oscillating bubbles and tissue may then be detected with appropriate pulse inversion sequences, where fundamental frequency suppression may be critical in the success of this technique.
5. ‘Bubble memory’ techniques, which use the subtraction of pulses of different lengths to isolate tissue and bubble signals, based on the assumption that the acoustic response of tissue is ‘memoryless’, whereas bubbles have ‘memory’, as described in the patent WO 2006/021400A1, which is incorporated herein by reference. Optimized subtraction, reducing the effect of a moving transducer relative to the tissue and contrast, of pulses is key to the success of this technique.
6. Combinations of above mentioned techniques.
These imaging approaches suffer even more from poor fundamental frequency suppression.